Dapsone (4,4'-diaminodiphenyl sulfone, DDS) and its repository form, acedapsone (4,4'-diacetamidodiphenyl sulfone, DADDS), have emerged as the most efficacious agents for treatment of leprosy. Both DDS and DADDS (through hydrolysis to DDS) exhibit high activity and low orders of toxicity at effective doses, and the emergence of organisms resistant to these drugs during therapy is infrequent. They are being administered to many of the estimated 10 million individuals suffering from leprosy throughout the world. Therefore, a clear understanding of the disposition and metabolic fate of these compounds is needed to provide a rational basis for their most optimal use. Recently, the antibiotic rifampin has been shown to be highly active in primary treatment and in the treatment of DDS-resistant leprosy. During the first six years of grant support, we have developed procedures for the accurate measurement of DDS, its monoacetylated derivative, MADDS, and DADDS in plasma; and DDS and MADDS and their conjugates in urine. Application of these techniques to different racial groups has shown that DDS is acetylated polymorphically. Recent work has suggested that the rapid acetylator characteristic combined with a rapid clearance of DDS from the body may predispose the emergence of DDS-resistant organisms in leprosy patients. Of the two species known to act as hosts for the in vivo multiplication of M. leprae, we found that the rat was a better model of man for metabolic studies. Our objectives are to extend our analytic capabilities to a study of tissue levels of DDS in mice, rats, and human subjects receiving DDS; to expand our capabilities for measuring DDS and its metabolites in urine to define completely the excretory patterns of DDS metabolites in man; and to initiate studies directed toward the development of selective and sensitive procedures for the measurement of rifampin and its metabolites in biological fluids of rats.